Current therapeutics for Alzheimer's disease (AD), the most prevalent cause of dementia, offer only modest curtailments in the progression of cognitive impairment. We propose to identify compounds that could serve as effective prophylactics or therapeutics for neurodegeneration. Aberrant expression of the nitric oxide synthase III (NOS III) gene are observed in the early stages of AD and various other neurodegenerative diseases. Elevated NOS III levels in these cases are associated with increased apoptosis, and experimentally, over-expression of NOS III in neuronal cells leads to apoptosis due to free radical injury. Moreover, even modestly increased NOS III levels enhance the susceptibility of neuronal cells to oxidative stress and free-radical injury. Ample evidence indicates that various natural products, including dietary ingredients and substances derived from herbs, may have beneficial antioxidant and other neuroprotective functions. These materials also offer the benefit of established safety profiles. Our hypothesis is that materials will inhibit NOS III-mediated cell death and could serve as neuroprotective agents. The objective of the Phase I application is to determine the utility of selected natural and related synthetic compounds in protecting vulnerable neurons from NOS III-mediated oxidative stress, using various screening tests specifically designed to asses neuronal viability and metabolic function. PROPOSED COMMERCIAL APPLICATIONS: Some 50-60% of individuals age 65 and over (about 4 million Americans) have Alzheimer's Disease (AD another 20% have Parkinson's or Lou Gehrig's Disease. The proportion of the US population that will be 65 or older is expected to increase exponentially. The AD patient population alone is expected to reach 14 million 2050. New, effective and safe therapeutics would constitute a major milestone in dementia treatment.